SUMMARY Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent and complex syndrome for which no etiological therapy is available. Osteopontin (OPN) is a matricellular protein that induces mitochondrial damage and oxidative stress in cardiac myocytes. OPN is upregulated in the circulation of HFpEF patients. Our work and preliminary data show that the Col4a3-/- mice, a model of kidney disease, display a HFpEF phenotype that includes cardiac diastolic dysfunction, hypertrophy, fibrosis, hypertension, and elevated renal and plasma levels of OPN. Our preliminary data reveals that mRNA and protein levels of 2-Oxoglutarate Dehydrogenase- Like (OGDHL), a Krebs cycle isoenzyme involved in OGDH complex formation and mitochondrial energy metabolism, is decreased in Col4a3-/- hearts. We found that double knockout Col4a3-/-OPN-/- mice have elevated cardiac OGDHL protein levels, and improved HFpEF phenotype. Dysregulated myocardial energetics in HFpEF patients is known to be a major contributor to disease progression. Therefore, using small and large animal models of HFpEF, we will test the hypothesis that upregulated OPN, released from the kidney, activates pathological signaling in the heart causing a decline in OGDHL and related ATP production contributing to the observed HFpEF phenotype in Col4a3-/- mice.